Abstract
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide [1]
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC)
We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3
Summary
Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide [1]. A genome-wide association study (GWAS) of HBV-related HCC was performed [6], in which 355 HBV– positive HCC patients and 360 chronic HBV carriers were used for the genome-wide discovery analysis, and the top 45 SNPs from the discovery analysis were further evaluated in additional 1,962 HBV–positive HCC patients and 1,430 controls (both chronic HBV carriers and population controls) as well as 159 trios. Further study with better design and bigger sample size was recommended for identifying additional susceptibility loci for HCC [7,8].
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